DESCRIPTION (Adapted from the application): The stimulus for this Program Project Grant (PPG) is the recent remarkable identification of >10 different pathogenic tau gene mutations in >20 distinct kindreds with autosomal dominant familial Frontotemporal Dementia (FTD) and Parkinsonism linked to chromosome 17 (FTDP-17). These landmark discoveries create bold new opportunities to elucidate cellular and molecular mechanisms of neurodegenerative diseases (tauopathies) characterized by prominent tau pathologies as well as the role of these pathologies in the progressive neuropsychiatric decline, brain degeneration and death of FTDP-17 patients, often before age 60. Significantly, insight into mechanisms of disease in FTDP-17 will clarify how brain degeneration occurs in more common tauopathies, including Alzheimer's disease (AD). Thus, this PPG capitalizes on the provocative discoveries of pathogenic tau gene mutations by pursuing multidisciplinary studies of the pathobiology of FTDP-17 and related tauopathies. The research interests of the investigators in this PPG converged prior to the discovery of the FTDP-17 mutations, and they now will work synergistically to develop an understanding of how abnormal tau gene regulation and tau protein dysfunction lead to the death of affected cells and diverse FTDP-17 phenotypes as well as seemingly sporadic FTDs. The goals of 4 projects in this PPG are to: 1. develop an understanding of the spectrum of clinical phenotypes that define sporadic FTDs, 2. identify new tau gene mutations and other abnormalities in tau gene regulation that cause FTDP-17 syndromes and sporadic FTDs, 3. elucidate how aberrant tau genes result in dysfunction (losses of normal functions, gains of toxic properties) of tau proteins and diverse tauopathies, 4. create transgenic mouse models of tauopathies and test hypotheses on mechanisms whereby tau pathologies lead to brain degeneration in tauopathies. Insights gained by this sophisticated, multidisciplinary team into the role of tau pathologies in mechanisms of brain degeneration in sporadic and familial tauopathies will hasten efforts to design better and more therapeutic interventions for these disorders, including AD, the most common tauopathy.